Project Summary This is a K01 application submitted by Dr. Rafael Guerrero-Preston in response to the funding opportunity announcement NCI Mentored Research Scientist Development Award to Promote Diversity (K01) - PAR-09- 052. Rafael, born and raised in Puerto Rico, is currently appointed as an Instructor at the Head and Neck Cancer Research Division of the Department of Otolaryngology at Johns Hopkins School of Medicine. Rafael's short term goals are to examine global, genome-wide and gene-specific epigenomic alterations in tumors that disproportionally burden African American and Latino communities: hepatocellular carcinoma, cervical cancer and head and neck cancers. Dr Guerrero-Preston's long-term goals are: to develop epigenomic biomarkers to improve Head and Neck Cancer (HNSCC) early detection and clinical management; and to contribute to the reduction of survival disparities in oral and oropharyngeal cancer. The proposed K01 project addresses two objectives relevant to the National Cancer Institute mission: to train culturally diverse cancer researchers; and to eliminate cancer health disparities. The overall HNSCC survival rates for African American patients in the United States has remained close to 20% higher than Whites for more than 30 years, but the biological basis for this disparity is poorly understood. A two-stage epigenomic study design is proposed to test the hypothesis that epigenetic alterations contribute to ethnic disparities in HNSCC survival by examining the following aims: Specific Aim 1: a) To assess differences of global DNA methylation across ethnic groups in tumor-surgical margins pairs of HNSCC patients (n=500); b) To quantify NID2 and HOXA9 differential methylation across ethnic groups in tumor-surgical margins pairs of HNSCC patients (n=500); c) To evaluate the association between differential methylation in tumor-surgical margin pairs, TP53 mutation status, and clinical outcome, including local recurrence and survival across ethnic groups. Specific Aim 2: a) To assess differences of global DNA methylation across ethnic groups in tumor tissue from HNSCC cases (n=300) and normal oral mucosa controls (n=300); b) To quantify NID2 and HOXA9 differential methylation across ethnic groups in tumor tissue from HNSCC cases (n=300) and normal oral mucosa controls (n=300); c) To evaluate the association between differential methylation in tissue and clinical outcome, including local recurrence and survival across ethnic groups. This K01 project strengths are multiple: mentorship by two world leaders in HNSCC genomics, David Sidransky and Wayne Koch; solid institutional support; use of world class research facilities in Johns Hopkins School of Medicine; and access to well characterized sample repositories - the ECOG E4393/RTOG 9614 study, a large multi-institutional head and neck cancer tumor-surgical margin study cohort with abundant outcome data; and a retrospective case-control study from samples stored by the Johns Hopkins Head and Neck Cancer SPORE